CN108236614A - Biological implantation for promoting hair tonic uses graft - Google Patents
Biological implantation for promoting hair tonic uses graft Download PDFInfo
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- CN108236614A CN108236614A CN201711418848.6A CN201711418848A CN108236614A CN 108236614 A CN108236614 A CN 108236614A CN 201711418848 A CN201711418848 A CN 201711418848A CN 108236614 A CN108236614 A CN 108236614A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
- A61K8/981—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of mammals or bird
- A61K8/982—Reproductive organs; Embryos, Eggs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/10—Hair or skin implants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
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Abstract
The present invention relates to the biological implantations comprising the stem cell with hair tonic functional cell cytokine secretion ability to use graft.
Description
Technical field
The present invention relates to hair tonic promotions to use graft.
Background technology
Hair plays a variety of effects, such as protection hair, the influence to extroversion, maintenance head temperature in human body, although
It is not that important organ is maintained to life, but is both the yardstick of health status and determines the important of the body of appearance
A part.Alopecia is considered as a series of aging phenomena, but it has recently been shown that, by various genetic elements and such as pressure, west
The eating habit of change, unbalanced nutrition, social activities many reasons such as variation lead to alopecia together.
Hair generates in hair follicle, and above-mentioned hair follicle is that skin is fallen into due to the proliferation of the duration of the stroma cell of scalp base portion
The structure entered has the hair cycle for including a variety of growth steps.Hair is according to 90% growth period for occupying normal hair
Catagen (catagen, the transitional of (anagen, growing phase), growth retardation and hair root atrophy
Phase), ball top it is dry and formed the stand-down (telogen, resting phase) of club hair and come off the phase (exogen) 4
Growth and alopecia is repeated in the growth cycle of kind step.
Alopecia reason is testis that heredity element and one of pressure and aging etc., representative mechanism are as androgen
Ketone (testosterone, T) is converted into dihydrotestosterone based on 5α-reductase (5 α-reductase, RD)
(dihydrotestosterone, DHT), so as to induce alopecia by the hair follicle of atrophy scalp.With advancing age, two
Hydrogen testosterone increases, and postpones the protein synthesis of hair follicle cell, thus, it is possible to which thinking the hair follicle ratio of stand-down increases and cause to take off
Hair carries out quickly.Also, it with aging, is destroyed, therefore dry thin from the stem cell of the nipple portion secretion keratin of hair follicle
The supply of born of the same parents is reduced.So as to promote alopecia.
The formation of hair has periodic cycle pattern.That is, by occupying 90% growth period of normal hair, growth stops
Stagnant and hair root atrophy catagen, ball top are dry and form the hair cycle of 4 kinds of steps such as the stand-down of club hair and the phase of coming off
(hair cycle), hair is constantly grown and alopecia.In particular, during catagen, many hair follicles carry out Apoptosis
(apoptosis), thus reduce into stand-down so as to the size of hair follicle.
The method developed to improve, treat these alopecia symptoms include smear promote hair tonic substance (synthetic,
Natural materials, cell culture fluid or its extract etc.), the method for transplanting hair, the method etc. for injecting the stem cell of oneself.Example
Such as, as alopeciaing therapeutic agent, minoxidil (minoxidil) coating agent is widely used, in Korean granted patent 10-1498201
Packet is disclosed in number and pitches loose algae extract as the Anti-hair loss of active ingredient or hair tonic improvement composition containing Constriction, in Korean granted
The Anti-hair loss comprising peanut bark extract or hair tonic composition for promoting are disclosed in patent 10-1484033.
Also, the treatment using stem cell medium is increasingly paid close attention to recently, but it is to be based on utilizing mesenchyma
Galore include trichogenous growth factor in the culture solution of stem cell.
However, these methods are due to hair root disappears in the case where needing to re-form hair follicle, there are its effect it is limited or
Need the difficulty smeared and injected repeatedly.Also, in order to re-form hair, it is important that the multiple relative growths of sustainable supply because
Son, but the method injected or smeared is only disposable, it is difficult to sustainable supply, mescenchymal stem cell is in duration growth
There are limitations.
For this purpose, process of the present inventor in the method for the growth factor needed for research in vivo sustainable supply growth
In, in the case where the stem cell cultivated under given conditions is transplanted using transplanting with graft, continue in vivo
Such as multiple stem cell growth promotive factors of basic fibroblast growth factor (bFGF) are supplied, are lured in the nipple portion of hair follicle
The growth of stem cell is led, so as to confirm the permanently effective effect of achievable stem cell, is had thus completed the present invention.
Invention content
The technical problem to be solved in the present invention
The object of the present invention is to provide for promote the biological implantation of hair tonic and/or improvement and hair growth transplant
Object.
Technical solution
To achieve these goals, the present invention is provided comprising the stem cell with hair tonic functional cell cytokine secretion ability
Biological implantation use graft.
Advantageous effect
The graft of the present invention is secreted in organism with the functional Multiple components of hair tonic, so as to length by transplanting
Time promotes hair tonic and improvement/hair growth.
Description of the drawings
Fig. 1 is to show to be cultivated the method for AF-N ((A) part of Fig. 1) using attached cell culture and injected AF-N special
The method ((B) part of Fig. 1) that Saite (theracyte) is drawn to cultivate.
Fig. 2 is the concentration (1 for showing basic fibroblast growth factor in the conditioned medium according to cultural method：Patch
The AF-N 1.0 × 10 of parietal cell culture5It is a；2：The AF-N 4 × 10 of attached cell culture5It is a；3：The AF-N of attached cell culture
1.0×106It is a；4：The AF-N 1.0 × 10 of theracyte injection cultures5It is a；5：The AF-N 4 of theracyte injection cultures ×
105It is a；6：The AF-N 1.0 × 10 of theracyte injection cultures6It is a).
Fig. 3 to Fig. 6 is to show respectively according to the (figure of basic fibroblast growth factor in the conditioned medium of cultural method
3), platelet-derived growth factor-AA (PDGF-AA) (Fig. 4), insulin-like growth factor (IGF) (Fig. 5) and without wing MMTV
The concentration (1 of integration site family member 7a (Wnt7a) (Fig. 6)：The AF-N 1.0 × 10 of attached cell culture5It is a；2：It is adherent thin
The AF-N 4 × 10 of born of the same parents' culture5It is a；3：The AF-N 1.0 × 10 of attached cell culture6It is a；4：The AF- of theracyte injection cultures
N 1.0×105It is a；5：The AF-N 4 × 10 of theracyte injection cultures5It is a；6：The AF-N 1.0 of theracyte injection cultures
×106It is a).
Fig. 7 is cell survival rate when showing to inject the stem cell of embodiment 1 to embodiment 4 into theracyte.
Fig. 8 is to show to confirm showing for the process of the Biofunctional for the theracyte for being injected with stem cell using mouse
It is intended to.
Fig. 9 is to transplant theracyte afterwards in first time epilation (plucking) to confirm the picture of hair tonic inducing effect.
Figure 10 is to transplant theracyte to confirm the picture of hair tonic inducing effect, at this point, only to true after pulling off the feather of at second
The multiple hypoxemia culture stem cells for recognizing hair-growing effects are compared.
Figure 11 is to transplant theracyte after third time is pulled off the feather of to confirm the picture of hair tonic inducing effect, at this point, only to true
The multiple hypoxemia culture stem cells for recognizing hair-growing effects are compared.
Figure 12 is to transplant theracyte after addition control group is pulled off the feather of in first time to confirm the picture of hair tonic inducing effect.
Figure 13 be in aging mice model first time pull off the feather of after transplanting theracyte come the anagen phase is induced into
The picture that row compares.
Figure 14 be after pulling off the feather of in aging mice model second transplanting theracyte come the anagen phase is induced into
The picture that row compares.
Figure 15 is the form for showing the inverse differentiation amniotic fluid stem cell inside theracyte after 9 days in transplanting tissue.
Figure 16 is the result for the hair follicle formation difference for analyzing every group of skin histology.
Figure 17 is the result dyed by the AP of every group of skin histology to measure HFDP cell activity.
Specific embodiment
The present invention relates to the biological implantation transplanting comprising the stem cell with hair tonic functional cell cytokine secretion ability
Object.
Also, the present invention relates to for improving the biological implantation preparation method of graft of alopecia, including that will have life
Send out stem cell injection step of the biological implantation in graft of functional cell cytokine secretion ability.
Also, the present invention relates to the preparation method of graft of the biological implantation for hair growth, including that will have life
Send out stem cell injection step of the biological implantation in graft of functional cell cytokine secretion ability.
Also, the present invention relates to for promoting the biological implantation of hair tonic with the preparation method of graft, including that will have life
Send out stem cell injection step of the biological implantation in graft of functional cell cytokine secretion ability.
Also, the present invention relates to alopecia ameliorative way, including by the graft transplantation of the present invention in the step of biology.
Also, the present invention relates to alopeciaing therapeutic method, including by the graft transplantation of the present invention in the step of biology.
Also, the present invention relates to hair tonic promote method, including by the present invention graft transplantation in biology step.
Also, the present invention relates to comprising functional thin with hair tonic for hair growth, improvement alopecia or promotion hair tonic
The biological implantation of the stem cell of the intracellular cytokine secretion capacity purposes of graft.
Hereinafter, the present invention is described in detail.
Stem cell with hair tonic functional cell cytokine secretion ability
Preferably, the stem cell with hair tonic functional cell cytokine secretion ability of the invention does carefully for amniotic fluid-derived
Born of the same parents.This is because amniotic fluid inner cell secretes growth hormone.And, it is preferable that of the invention has the hair tonic functional cell factor
The stem cell of secretion capacity is inverse differentiation amniotic fluid stem cell.And, it is preferable that of the invention has the hair tonic functional cell factor
The stem cell of secretion capacity is embryonic origin mescenchymal stem cell.It is highly preferred that the present invention have hair tonic functional cell because
The stem cell of sub- secretion capacity is the inverse differentiation mescenchymal stem cell of embryonic origin.
Above-mentioned inverse differentiation stem cell is made using known inverse differentiation method, this is not particularly limited.For example,
The inverse differentiation stem cell of the present invention can be made by that will import mescenchymal stem cell against differentiation factor.To this inverse differentiation factor
Also it is not particularly limited, it is preferable that considering safety and efficiency, utilizes what is be verified.For example, inverse point of the present invention
Changing stem cell can be prepared by the use of Oct4, Klf, Myc, Sox, Nanog as inverse differentiation factor etc., it is preferable that this
The inverse differentiation stem cell of invention can be made using Nanog genes.Compared with the stem cell of not inverse differentiation, inverse differentiation of the invention is done
Cell is characterized in that, is increased growth time, is increased growth division number, promotes growth factor secretion.
The above-mentioned hair tonic functional cell factor refer to have effects that hair tonic promotes, alopeciaing therapeutic effect, alopecia inhibit effect,
Alopecia improves the cytokine profiles of effect.Above-mentioned cell factor may be selected from by basic fibroblast growth factor, blood platelet
Derivative growth factor-AA, insulin-like growth factor and without wing MMTV integration site family members 7a composition group in.
Preferably, above-mentioned stem cell is the stem cell cultivated under hypoxia condition.At this point, hypoxia condition refers under atmospheric pressure
Less than the oxygen condition of oxygen concentration, it is preferable that refer to the condition that oxygen concentration is 0.01% to 8%, it is highly preferred that referring to 0.05% to 5%
Condition, it is further preferred that referring to 0.10% to 3% condition.
It is cultivated at this point, culture can be biological implantation with culture in graft or general attached cell, preferably
It is cultivated for general attached cell.
Biological implantation uses graft
The biological implantation (transplantation) of the present invention is to be gathered by the film of biocompatibility film preparation with graft
Close object cavity.Above-mentioned biological implantation is the container for being transplanted in biology with graft, that is, as biological implantation container, is had
The space of stem cell can be injected, many kinds of substance made of stem cell is secreted outside graft by film, it is especially multiple thin
Intracellular cytokine.Above-mentioned graft protection refusal receives the object of stem cell transplantation, when transplanting is when subcutaneous, it is preferable that have induction
Close to the angiogenesis function of the formation of the capillary of film.By above-mentioned angiogenesis function, graft does into film
Cells with nutrient and blood.Preferably, above-mentioned graft by biological environmental production material preparation, that is, it is immune anti-by not causing
The material preparation answered.This material is well known materials, for example, polyurethane etc..Preferably, above-mentioned graft has multiple pore positions
Porosity surface in surface, at this time, it is preferable that the size in hole is that cannot pass through the substance that such as cell size is big but can make
The size that protein or nutrient come in and go out.Therefore, the stem cell in graft can be flow by above-mentioned hole without normal direction implantation material
It goes out outside, prevents the cancer induced by stem cell, on the other hand, multiple growth promoting factors as stem cell secretion object are discharged into
In blood, blood vessel is thus formed around, oxygen and nutrient are supplied into graft.It is shown during the survival of stem cell as a result,
Writing increases.Also, above-mentioned graft is also readily removable after long-time after the transfer.Above-mentioned graft is used purchased from satisfaction
The market products of above-mentioned condition.For instance, it is preferred that above-mentioned graft is theracyte (TheraCyteTM)。
The biological implantation of the present invention is used to treat or improves alopecia with graft.Also, the biological implantation of the present invention moves
Plant is used to promote hair tonic.At this point, the biological implantation of the present invention can be used for treatment or improve to take off as caused by aging with graft
Hair.Also, the alopecia as caused by aging can be used for promoting by the patient of pain, biological implantation of the invention with graft
Hair tonic.
The biological implantation of the present invention may include 1.0 × 10 with graft3It is a to 1.0 × 1010The stem cell of a present invention, this
When, the stem cell of culture is injected in graft in itself.However, the present invention is to make stem cell from the long-time work in biology
Make rather than will stem cell culture solution injection graft in.By transplanting of the stem cell injection with permeable membrane of the present invention
It is transplanted in object, is because oxygen and the nutrition to required consumption can be received by the blood for the object being transplanted.Also, because
For compared with injecting culture solution into graft, inject more stem cells to promote hair tonic and to prevent/improve/hair growth more
Effectively.
The present invention can be planted by injecting the biological implantation of the present invention with the stem cell of the present invention of graft, from
And hair can be promoted and formed, without having the risk for generating immunological rejection or generating cancer cell.
Preferably, the biological implantation of the present invention is planted with graft in organism, it is preferable that plant under scalp (skin
Under).At this point, it is animal including people to receive transplanting biological implantation of the invention with the object of graft, especially because de-
Send out the people to meet difficulty.
Step of the biological implantation in graft will be injected with the stem cell of hair tonic functional cell cytokine secretion ability
The present invention relates to for promoting the biological implantation of hair tonic/hair growth/improvement alopecia/inhibition alopecia with graft
Preparation method, including that will have the stem cell of hair tonic functional cell cytokine secretion ability to inject biological implantation in graft
Step.Above-mentioned method for implanting using existing graft inner cell method for implanting, is not particularly limited in itself.
It can be allowed with reference to aftermentioned embodiment and advantages of the present invention, feature and realize that the method for these advantages and features is brighter
Really.But the invention is not limited in embodiment as disclosed below, can by it is mutually different it is various in a manner of implement, this reality
Applying example makes disclosure of the invention complete, for general technical staff of the technical field of the invention to be made to be fully understood by the present invention
Scope, the present invention only defines by inventing claimed range.
<Material and method>
Experimental animal
As experimental animal, the C57BL/6 mouse of 6 week old have been used.On the other hand, in order to which Ageing Model is tested and uses
The C57BL6 mouse models of agings more than 13 week old.
Import the inverse differentiation reactivation mescenchymal stem cell of Nanog amniotic fluid-deriveds
The inverse differentiation reactivation mescenchymal stem cell (Reprogrammed of amniotic fluid-derived established by importing Nanog genes
amniotic fluid-derived mesenchymal stem cell with nanog；Below be AF-N) preparation such as
Under, that is, Nanog channel genes and are induced in the mescenchymal stem cell of amniotic fluid-derived embryo using retroviral vector
The overexpression of Nanog genes.Hereinafter, the inverse differentiation reactivation mesenchyma of amniotic fluid-derived established by importing above-mentioned Nanog genes
Stem cell is known as " AF-N ".
The culture of stem cell
Amniotic fluid stem cell culture is in the FBS comprising DMEM, 10%, 1% P/S, 1% L-Glutamine (L-
Glutamine), the dimension life of the basic fibroblast growth factor of 4ng/ml, the selenium (selenium) of 5ng/ml, 50ug/ml
In the culture medium of plain C (vitamin C).
It is injected in the theracyte of amniotic fluid stem cell
In the Tissue Culture Dish of 100mm, each amniotic fluid stem cell group is cultivated, until covering 70~80%
After until the surface of adhere-wall culture container, cell number is counted and by 1.0 × 107A cell is suspended in the low grape of 20 μ l
Sugar (low-glucose) DMEM, using 22G needles (needle) injection (injection) in theracyte.Then, with strength
First binding agent seal entrance.
Theracyte transplants (transplantation)
After anesthetized mice, after beating the hole of 10mm or so on the right side of back, theracyte is inserted into its inside.Then, with seam
It shares silk suture or is sewed up a wound using wound clip (wound clip).
Cell counting Kit (Cell Counting Kit, CCK)
After secreting out of the theracyte being transplanted by sacrificing the mouse for being included in experimental group, rear side is cleaned with PBS
It is external.Then, it is cultivated 30 minutes after mixing the Cell counting Kit of (mix) AF growth mediums and 100ul.Recycling
(harvest) absorbance (absorbance) is measured under the wavelength of 450nm after the culture medium of culture.
<Embodiment 1>
(Normoxia) culture does not import the amniotic fluid stem cell of Nanog genes and obtains amniotic fluid under conventional aerobic conditions
Stem cell.
<Embodiment 2>
The culture AF-N (the inverse differentiation amniotic fluid stem cell established by importing Nanog genes) under conventional aerobic conditions
And obtain amniotic fluid stem cell.
<Embodiment 3>
The amniotic fluid that oxygen concentration does not import Nanog genes to be cultivated under the conditions of 1% hypoxgia (Hypoxia) (hypoxemia) is done carefully
Born of the same parents simultaneously obtain amniotic fluid stem cell.
<Embodiment 4>
Culture AF-N (inverse point established by importing Nanog genes under the conditions of the hypoxgia (hypoxemia) that oxygen concentration is 1%
Change amniotic fluid stem cell) and obtain amniotic fluid stem cell.
<Experimental example 1>Confirm the cell factor basic fibroblast growth factor point for the AF-N for flowing into theracyte
It secretes
To hair tonic functional cell factor alkalinity in the conditioned medium obtained of the cultural method based on AF-N into fibre
The concentration difference of dimension Porcine HGF is evaluated.Specifically, it is 1.0 × 10 to change AF-N stem cells respectively5It is a, 4 ×
105It is a, 1.0 × 106It is a, it is cultivated in the attached cell using the general stem cell culture method as them
Situation ((A) part of Fig. 1) and AF-N is injected in theracyte in the situation ((B) part of Fig. 1) cultivated, utilized
Enzyme-linked immunosorbent assay (ELISA) analysis method measures basic fibroblast growth factor in each conditioned medium
Concentration.
As a result, in the case where being cultivated using attached cell culture (attached cell culture), alkalinity
The concentration of fibroblast growth factor increases with the increase of cell number, but AF-N injections theracyte is trained
In the case of supporting, the secretory volume of basic fibroblast growth factor does not increase with the increase of cell number, CMC model
The concentration of base (conditioned media) interior basic fibroblast growth factor is kept constant (Fig. 2).
In the case where AF-N injections theracyte is cultivated, cultivated with usually general using attached cell
Carry out cell culture it is similar, it is meant that the hair tonic functional cell of the stem cell secretion injected inside theracyte because
Son is by the film of theracyte to external secretion.It is thus identified that theracyte does not limit hair tonic functionality, it can be used as preparation for baldness
Transfer unit.
On the other hand, in the case that AF-N injections theracyte is cultivated, basic fibroblast growth factor
Secretory volume is kept constant to be without the reasons why big variation, 1) since stem cell growth is inside so-called theracyte
The space of limitation, thus the metabolism of cell compared with the situation that attached cell is cultivated there may be difference or 2)
Theracyte is not only spatially restricted, but also the channel of releasable cell factor is also restrained, due to the bottle of channel
Neck phenomenon, passable amount may be restricted within given time.
Therefore, in the case that AF-N injections theracyte is cultivated, confirmed by further experiment, it is alkaline into fibre
Whether the reason of tieing up constant concentration in the conditioned medium of Porcine HGF be because cell factor can be led to by theracyte films
The saturation for the amount crossed.
<Experimental example 2>Confirm the hair tonic functional cell cytokine secretion for the AF-N for flowing into theracyte
In above-mentioned experimental example 1 in the case where AF-N injections theracyte is cultivated, basic fibroblast is confirmed
Whether because cell factor can be passed through by theracyte films the reason of constant concentration in the conditioned medium of Porcine HGF
Amount saturation, when transplanting in mouse when, in order to determine will flow into theracyte the number of stem cell, with above-mentioned experimental example 1
Identical method culture AF-N measures the concentration of multiple hair tonic functional cell factors in obtained conditioned medium.Many institutes
It is known, at this point, the multiple cell factors measured as basic fibroblast growth factor, platelet derived growth factor-
AA, insulin-like growth factor and without wing MMTV integration site family member 7a, they are the growth factors for promoting hair tonic.
As a result, platelet-derived growth factor-AA and situation without wing MMTV integration site family members 7a also with
The situation of basic fibroblast growth factor is similar, in the case where attached cell is cultivated, with the increasing of the cell number of injection
Add, the amount of the cell factor of release increases, and in the case where culture is in theracyte, observed carefully although confirming
Intracellular cytokine amount increases, but compared with attached cell is cultivated, increasing degree is relatively few.
In contrast, in the case of insulin-like growth factor, spread out with basic fibroblast growth factor, blood platelet
Growth factor-AA is given birth to, without wing MMTV integration site family members 7a differences, under attached cell condition of culture, with cell number
Increase it is unrelated, can be observed concentration keep constant after reduce, culture in theracyte under conditions of, confirm with
The increase for the cell number injected, the concentration of insulin-like growth factor is continuously increased (Fig. 3 in conditioned medium：Alkalinity is into fibre
Tie up Porcine HGF；Fig. 4：Platelet-derived growth factor-AA；Fig. 5：Insulin-like growth factor；Fig. 6：Without wing MMTV
Integration site family member 7a) (1：The AF-N 1.0 × 10 of attached cell culture5It is a；2：AF-N4 × 10 of attached cell culture5
It is a；3：The AF-N 1.0 × 10 of attached cell culture6It is a；4：AF-N1.0 × 10 of theracyte injection cultures5It is a；5：
The AF-N 4 × 10 of theracyte injection cultures5It is a；6：The AF-N 1.0 × 10 of theracyte injection cultures6It is a).
Therefore, it can determine whether that the channel for the cell factor that can be discharged out of theracyte does not reach saturation state.Therefore,
Think the concentration of conditioned medium based intracellular cvtokine does not increase with the increase for the cell number for flowing into theracyte, is
Because the spatiality limitation of so-called theracyte does not influence the metabolism of stem cell.
Summary, in vitro under environmental condition, as the cell number for flowing into theracyte increases, some hair work(
The measured value of energy property cell factor increases, and in vivo under (in vivo) state, and serum is thin to doing by theracyte films
Born of the same parents supply, and thus make the metabolic activity of stem cell and releasable more cell factors, therefore, will flow into theracyte
Cell number be set in suggestion amount most 1.0 × 107It is a, it is tested after carrying out.That is, in vivo studies later, it will
1.0×107After a stem cell injection theracyte, transplant and tested after mouse.
<Experimental example 3>Theracyte inner cells survival ability is evaluated
The stem cell of embodiment 1 to embodiment 4 is injected separately into 1.0 × 10 in theracyte7After a, transplant in
The skin of C57BL/6 mouse models.Moreover, after transplanting 14 days, recycle the theracyte being transplanted and tried using cell count
Agent box evaluates indivedual stem cells of injection.
Cell counting Kit can by with high water-soluble tetrazolium (tetrazolium) salt (WST-8) by nicotinoyl
Amine adenine-dinucleotide phosphoric acid/reduced nicotinamide adenine dinucleotide phosphate dehydrogenase (NADP/NADPH
Dehydrogenase it) restores and the formazan dye (formazan dye) that discharges and the color change that occurs, measures cell
Survival ability (viability).
Also, (1) is used in the situation (being labeled as theracyte) measured using theracyte (biological implantation container)
And (2) are put into 1.0 × 10 in theracyte7Situation that a amniotic fluid-derived mescenchymal stem cell (AF) directly measures afterwards (as
Positive controls, labeled as positive (Positive)) it is compared.The above situation (1) is that AF is put into theracyte not
It transplants in mouse, and AF is put into after theracyte the stem cell survival ability that directly measures, the above situation (2) is not lead
Enter Nanog genes, and the amniotic fluid stem cell cultivated under conventional aerobic conditions is put into theracyte's.That is, the above situation
(1) and (2) are the groups do not transplanted in mouse.
As a result, compared with situation about being measured with being not injected into cell merely with theracyte, embodiment 1 to embodiment 4
Amniotic fluid stem cell have high cell viability measurement measured value, this be mean transplanting 14 days after stem cell also survive.And
And this is that the stem cell for meaning to be injected is protected by theracyte films, thus not by immunological rejection.
On the other hand, be respectively compared embodiment 1 to embodiment 4 is higher than amniotic fluid as a result, having against differentiation amniotic fluid stem cell
The survival ability of stem cell, compared with conventional oxygen concentration, the stem cell cultivated under the aerobic conditions of low concentration has higher
Survival ability.
In the case of the amniotic fluid stem cell of embodiment 3, though transplanting 14 days after be determined, but in routine
Aerobic conditions under the embodiment 1 cultivated compare, without what big difference.Therefore, judge to cultivate under low oxygen conditions inverse
Differentiation amniotic fluid stem cell is most suitable for exploitation into alopeciaing therapeutic agent (Fig. 7).
<Experimental example 4>
Utilize main for confirming in the functional C57BL/6 mouse of hair, since the melanin of formation pigment is thin
Born of the same parents exist only in hair follicle, may be not present in epidermis, therefore with the characteristic that the colour of skin is determined by the amount of melanin.It is black in hair follicle
Pigment synthesis only carries out in growth period, therefore in the growth period colour of skin in black, and not synthesis of melanin catagen and stop
Phase pinkiness has the advantages that also to confirm hair cycle by the colour of skin without tissue examination.
In the present invention, 1.0 × 10 are injected in theracyte7The amniotic fluid stem cell of a embodiment 1 to embodiment 4,
After carrying out first time epilation, transplanted in the C57BL/6 mouse for carrying out second of anagen phase (anagen phase) above-mentioned
Theracyte simultaneously evaluates hair tonic functionality.At this point, will not carry out the mouse (untreated fish group) of any sample pretreating as
Control group observes the Growth trends of hair.Fig. 8 is the schematic diagram for confirming this mouse in vivo functionality process.
It is the results show that with other multiple experimental group (embodiment 1 and embodiment 2, untreated fish group as a control group) phases
Than, in the case that the amniotic fluid stem cell of embodiment 3 and embodiment 4 injection theracyte is transplanted, hair tonic functional result
Bigger (Fig. 9).
It is interpreted as, because influencing hair tonic function to the increase associativity of the secretory volume of cell factor under low oxygen conditions
Property.On the other hand, because the transplanting of theracyte has animal model very big wound, and this is because can influence hair tonic
Functional part, therefore pull off the feather of after wound healing, then hair tonic functionality is evaluated again.
As above it is determined, after wound healing, the result observed after being pulled off the feather of confirms, after second is pulled off the feather of, with
Control group is compared, and with first time epilation, is injected the amniotic fluid stem cell of embodiment 3 and embodiment 4 since the 7th day
In the case that theracyte is transplanted, there is apparent growth period induction (anageninduction) (Figure 10).
Also, third time epilation is carried out, observes hair inducing effect, is occurred with carrying out first time epilation and pulling out for the second time
Result as hairs.That is, compared with the control group, embodiment 3 and embodiment 4 are injected in the case that theracyte transplanted,
There is growth period Inducement difference since transplanting the 8th day, after the 12nd day, become apparent from.Also, with carrying out first time epilation and the
Situation about being transplanted after secondary epilation is compared, and observes that region (area) size for carrying out growth period (anagen) broadens, in particular, with
Embodiment 3 is compared, and in the case of the inverse differentiation amniotic fluid stem cell of injection embodiment 4, confirms growth term area (anagen
Area) increased bigger (Figure 11).
If stem cell is injected theracyte and transplanted by comprehensive these as a result, can confirm, hair tonic Z can be continuously maintained
Functional result.In particular, in the case of the inverse differentiation amniotic fluid stem cell cultivated under the hypoxia condition of injection embodiment 4, confirm
Hair tonic functional result is fitst water.
<Experimental example 5>
Several control groups are added to be tested in an identical manner in multiple experimental groups of above-mentioned experimental example 4.Specifically,
The situation that unimplanted stem cell is only transplanted to Theracyte is set as additional negative control group and (only transplants Theracyte
(theracyte only)), so as to can confirm the wound generated due to the transplanting of Theracyte functional influence on hair tonic.
It also, daily will inverse differentiation amniotic fluid stem cell culture solution (stem cell number：1.0×107It is a) be applied to mouse skin situation
It uses (smearing) as a control group.Also, it utilizes to the suitable wound clip of the suture of big wound, it is effective to allow to carry out
Wound suture.In addition to this, the condition identical with above-mentioned experimental example 5 and method are tested.Embodiment 1 to embodiment 4 is done
Cell is also identical with experimental example 4, is carried out by calculating, so that the cell number for flowing into Theracyte is about 1.0 × 107It is a.
It is transplanted as described above in the C57BL/6 mouse for carrying out second of anagen phase after carrying out first time epilation.
As a result, it is identical with experimental example 4, when using theracyte, it Z can be continuously maintained the hair tonic functionality effect of stem cell
Fruit in particular, again flowing into the inverse differentiation amniotic fluid stem cell of embodiment 4 in the case that theracyte transplanted, confirms hair tonic
Effect is fitst water (Figure 12).
<Experimental example 6>
Based on above-mentioned experimental result, the inverse differentiation amniotic fluid stem cell for flowing into theracyte can have hair tonic functionality.Cause
This, utilizes the mouse alopecia mould of the aging with the characteristic similar with the advanced age hair loss patient that many depilation phenomenons actually occur
Type evaluates hair tonic ability.
For this purpose, the C57BL6 mouse of agings more than 13 week old are prepared.Untreated above-mentioned mouse model also has voluntarily
The feature of alopecia is carried out, simultaneously because growth cycle of hair and judgement are easy, therefore judges to be suitble to this experiment.(McMahon
WM, Sundberg JP.Animal Models and Biomedical Tools, ed.Sundberg JP, pp.493-
497.CRC Press, Boca Raton, FL, 1994.).
Specific experimental method is identical with above-mentioned experimental example 4 and experimental example 5.In this experiment, by unimplanted stem cell and
Only transplanting Theracyte situation be set as additional negative control group (only transplanting Theracyte) so that can confirm because
The transplanting of Theracyte and the wound functional influence on hair tonic generated.It is also, the stem cell medium of embodiment 4 is (dry
Cell number：1.0×107It is a) be applied to mouse skin situation be used as control group (embodiment 4- smearings).Moreover, with implementation
Example 4 is identical, is carried out by calculating, so as to be by the cell number of the stem cell of embodiment 2 and embodiment 4 injection theracyte
About 1.0 × 107It is a.As above institute is carried out in the C57BL/6 mouse for carrying out second of anagen phase after carrying out first time epilation
The transplanting stated.
As a result, group phase with only smear theracyte and embodiment 4 identical with the result of multiple experimental examples before
Than in the case of the embodiment 2 and embodiment 4 for flowing into theracyte, confirming that growth period induction carries out quickly (to scheme
13).This is meaned compared with amniotic fluid stem cell, the hair tonic functionality higher of inverse differentiation amniotic fluid stem cell.
<Experimental example 7>
Confirm that the theracyte of the inverse differentiation amniotic fluid stem cell comprising the present invention is also old by the result of above-mentioned experimental example 6
It is effective in the model of change.Therefore, in order to understand the functional aberrancy in the growth period in the model of more aging, progress is utilized
19 week old of the Ageing Model of above-mentioned experimental example 6 after 6 weeks (restart after the model experiment of existing 13 week old by growth period
19 week old after 6 weeks) second of epilation experiment of mouse model progress.
As a result, compared with the situation of experimental example 6, as a result significantly, because mouse model aging control group situation
Under, compared with the slow phenomenon of partial development that growth period induction occurs in the progress with alopecia, in the group of plantation theracyte
In the case of, the secretion because of the duration of the germinal cell factor and functional expression are determined, is gone out with time going by
Now big difference.Its result implies, compared with conditioned medium is applied to skin, the cell that is present in inside theracyte
Secretion (secretome) effect bigger.This hair-growing effects are identical with the result in embodiment 6, embodiment 3
(theracyte) and the group effect of embodiment 4 (theracyte) is best, secondly embodiment 4- smearing groups, are only transplanted
The effect of Theracyte groups is worst (Figure 14).
<Experimental example 8>
As described above, it confirmed the survival of amniotic fluid stem cell group by Cell counting Kit.In order to reaffirm, carry out
Confirm the experiment which kind of amniotic fluid stem cell group survived inside the theracyte in the form of.At this point, theracyte samples use
The sample of the 7th day in embodiment 7 has carried out H＆E dyeing by cutting inside (section) theracyte.
As a result, in the only tissue of transplanting theracyte, inside exists nothing.In contrast, implement in injection
Stem cell is confirmed in the theracyte inside of the stem cell of example 2 and embodiment 4 to be texturized (Figure 15).It has authenticated as a result, thin
Intracellular growth and survival about 6 weeks or more and persistently functioning property.
<Experimental example 9>
In experimental example 6 and experimental example 7, have authenticated and induced by the exterior section growth period of aging mice model.Therefore,
By fabric analysis, confirmation has been actually formed hair follicle.For this purpose, the experiment in embodiment 7 carries out the 5th day, by aging mice
The skin histology of model is sampled and is analyzed.
As a result, a large amount of hair follicle tissue is confirmed in the skin histology of theracyte groups (embodiment 2 and embodiment 4),
Confirm compared with the form in the growth period of early period, growth period is also the hair follicle form that a large amount of late growth phase is distributed with.With this
On the contrary, there is the HFDP groups of cells that can largely become hair follicle in 4 smearing group of embodiment, but before being in relatively in growth period
Phase, therefore judge functionally compared with theracyte groups, relatively poor (Figure 16).
<Experimental example 10>
In order to reaffirm above-mentioned experimental example 9 as a result, to it is each tissue carry out AP dyeing, measure HFDP cells activity
Degree.In this test, higher for the activity degree of hair formation, the positive part occurred by AP dyeing is greatly and apparent.
As a result, it can visually confirm compared with the only group of transplanting theracyte, the group for the stem cell for smearing embodiment 4, note
The HFDP degree of activation of cells for entering the theracyte groups of the stem cell of embodiment 2 and embodiment 4 is more excellent (Figure 17).
Therefore, it can confirm that theracyte can make stem cell from immune response, meanwhile, pass through paracrine action
(paracrine effect) increases its functionality.
Claims (13)
1. a kind of biological implantation is with graft, which is characterized in that includes dry with hair tonic functional cell cytokine secretion ability
Cell.
2. biological implantation according to claim 1 is with graft, which is characterized in that for treating or improving alopecia.
3. biological implantation according to claim 1 is with graft, which is characterized in that for promoting hair tonic.
4. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned hair tonic functional cell factor choosing
Free basic fibroblast growth factor, platelet-derived growth factor-AA, insulin-like growth factor and without wing MMTV
In the group of integration site family member 7a compositions.
5. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned stem cell is to be trained under hypoxia condition
Foster stem cell.
6. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned stem cell is from amniotic fluid
Stem cell.
7. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned stem cell does for inverse differentiation amniotic fluid
Cell.
8. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned stem cell is from embryo's
Mescenchymal stem cell.
9. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned biological implantation is included with graft
1.0×103It is a to 1.0 × 1010A above-mentioned stem cell.
10. biological implantation according to claim 1 is with graft, which is characterized in that is implanted under scalp.
11. biological implantation according to claim 1 is with graft, which is characterized in that above-mentioned biological implantation is used with graft
In treatment or improve the alopecia as caused by aging.
12. a kind of biological implantation preparation method of graft for being used to improve alopecia, which is characterized in that including that will have hair tonic
Stem cell injection step of the biological implantation in graft of functional cell cytokine secretion ability.
13. a kind of biological implantation for hair growth preparation method of graft, which is characterized in that including that will have hair tonic
Stem cell injection step of the biological implantation in graft of functional cell cytokine secretion ability.
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| WO2016138025A2 (en) | 2015-02-23 | 2016-09-01 | Tissuetech, Inc. | Apparatuses and methods for treating ophthalmic diseases and disorders |
| CA2984443A1 (en) | 2015-05-20 | 2016-11-24 | Tissuetech, Inc. | Compositions and methods for preventing the proliferation and epithelial-mesenchymal transition of epithelial cells |
| TW201733600A (en) | 2016-01-29 | 2017-10-01 | 帝聖工業公司 | Fetal support tissue products and methods of use |
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